title: Lithium reduces tumorigenic potential in response to EGF signaling in human colorectal cancer cells.
abstract: Lithium is a specific inhibitor of GSK3-β, and hence, an activator of the Wnt/β-catenin pathway, whereas the epidermal growth factor (EGF) has been linked to malignant transformation in epithelial cancer cells. Both pathways are aberrantly activated in most colorectal cancers (CRCs). However, the relationship between them in modulating events related to the progression of this cancer type remains to be defined. In this study, we investigated whether the Wnt/β-catenin and EGFR pathways converge to modulate the malignant potential of CRC. We used Caco-2 cells, a well-established model used to study CRC, and treatments with lithium chloride, as a modulator of the Wnt/β-catenin pathway, and with EGF as an inducer of EGFR signaling. We found that both agents altered the subcellular distribution of claudin-1 and β-catenin, two important proteins of the apical junctional complex, but not their abundance in the cell. Nuclear stabilization of β-catenin, a marker of Wnt pathway activation, was observed after treatment with both compounds. However, lithium, but not EGF, inhibited GSK3-β, indicating that these agents modulate this enzyme in a differential fashion. Furthermore, EGF treatment increased the proliferative and migratory capacity but did not alter the colony formation potential of these cells. Surprisingly, lithium, known to activate the Wnt/β-catenin pathway, inhibited the increased proliferation by arresting cells in the G2/M phase as well as the cell migration promoted by EGF, as demonstrated by the combined treatment with these agents. Lithium treatment alone reduced the cell colony formation. Thus, our findings suggest that lithium plays an important role in regulating cellular events related to tumor progression in CRC.
authors.affiliation: Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional do Câncer, Rua André Cavalcanti 37, 5° Andar, Rio de Janeiro CEP 20230-051, Brazil.
authors.forename: Flávia
authors.initials: F
authors.lastname: Vidal
authors.forename: Wallace Martins
authors.initials: WM
authors.lastname: de Araujo
authors.forename: André L S
authors.initials: AL
authors.lastname: Cruz
authors.forename: Marcelo Neves
authors.initials: MN
authors.lastname: Tanaka
authors.forename: João P B
authors.initials: JP
authors.lastname: Viola
authors.forename: José A
authors.initials: JA
authors.lastname: Morgado-Díaz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D062445:Claudin-1; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C568108:CLDN1 protein, human; C495270:CTNNB1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D004815:Epidermal Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride